A large number of cellular processes involve major membrane remodeling events, such as bilayer fusion or scission, which are energetically costly and require additional protein machinery to proceed efficiently. This is the case for influenza A virus budding, which was recently shown to require the membrane embedded M2 ion channel. Here, we propose to develop a multiscale computational model, coupled with experiments, to quantitatively study protein-mediated large-scale changes in membrane morphology. The fundamental computational challenge is to accurately and efficiently couple the dynamics of the membrane to those of the membrane proteins, which can be thousands of times smaller. First, we will construct a flexible, phase field model of the membrane at the micrometer length scale in which lipid components and membrane proteins, such as the M2 proton channel, are described by time-dependent probability distributions that diffuse on the surface of the membrane and influence the local membrane mechanical properties (Aim 1). Next, the model will be parameterized at the nanometer scale through the use of fully-atomistic and hybrid continuum-atomistic methods to reveal how individual M2 channels alter membrane properties (Aim 2). Finally, the large-length scale model in Aim 1 will be further parameterized through experimental studies that will quantitatively measure the energetics of M2 channel related peptides partitioning between different ordered and disordered membrane phases (Aim 3). Our computational approach will allow efficient simulations of membrane deformation and topological changes on spatial and temporal scales that are not currently possible using conventional methodologies. Our integrated computational and experimental analysis will address fundamental biophysical and medical questions related to protein driven membrane curvatures, and it will elucidate how these processes are affected by lipid composition, protein structure, and lipid-protein interactions. Our simulation techniques will have widespread applicability to the viral exit step used by HIV and Ebola as well as the initial entry step for ths class of viruses, which involves protein-mediated coalescence of the viral and host cell membranes.
Protein-mediated membrane scission is an essential step in the life cycle of enveloped viruses (HIV, Ebola, Influenza), and our work has the potential to discover new therapies for influenza by blocking M2 channel mediated scission at this final step. Additionally, the similarity between M2 and antimicrobial peptides suggests that our work may reveal how to better design small agents to disrupt bacterial membranes.
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